Automated system for handling microfluidic devices

ABSTRACT

The present invention is an automated microfluidic chip processing apparatus that includes a deck for holding at least one microfluidic chip and capable of being accessed by a liquid handling system, a fluid control system, and a detection system, wherein a chip handling device transports the chip from the deck to the fluid control system and the detection system. The present invention also includes a chip for use with an automated microfluidic chip processing apparatus, and a method for processing a microfluidic chip using such an apparatus.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of and is a divisional of U.S.patent application Ser. No. 11/133,943, filed May 20, 2005, andincorporated herein in its entirety by reference.

FIELD OF THE INVENTION

This invention is generally directed to microfluidic chip devices and anautomated apparatus for providing small volume, multifunction labprocedures on microfluidic chips.

BACKGROUND OF THE INVENTION

The use of microfluidic technology has been proposed for a number ofanalytical chemical and biochemical operations. This technology allowsone to perform chemical and biochemical reactions, macromolecularseparations, and the like, that range from the simple to the relativelycomplex, in easily automated, high-throughput, low-volume systems. Theterm “microfluidic” refers to a system or device having micron orsubmicron scale channels and chambers. In general, microfluidic systemsinclude a microfluidic device, or chip, that has networks of integratedsubmicron channels in which materials are transported, mixed, separatedand detected. Microfluidic systems typically also contain componentsthat provide fluid driving forces to the chip and that detect signalsemanating from the chip.

Microfluidic chips may be fabricated from a number of differentmaterials, including glass or polymeric materials. An example of acommercially available microfluidic chip is shown in FIG. 1. FIG. 1A isa topside view of the chip, and FIG. 1B is a bottom side view of thesame chip. That chip, a DNA LabChip® manufactured by Caliper LifeSciences, Inc. of Mountain View Calif., is used with the Agilent 2100Bioanalyzer system manufactured by Agilent Technologies, Inc. of PaloAlto Calif. The chip in FIG. 1 has two major components: a working part128 made of glass, and a plastic caddy or mount 127 bonded to theworking part. The working part contains microfluidic channels in itsinterior, and wells on its exterior that provide access to themicrofluidic channels. The working part is typically fabricated bybonding together two or more planar substrate layers. The microfluidicchannels in the working part are formed when one planar substrateencloses grooves formed on another planar substrate. The mount protectsthe working part of the chip, and provides for easier handling of thechip by a user. The increased ease of handling partially results fromthe fact that the mount 127 is larger than the working part of thedevice, which in many cases is too small and thin to be easily handled.The mount may be fabricated from any suitable polymeric material, suchas an acrylic or thermoplastic. The glass working part is typicallybonded to the polymeric mount using a UV-cured adhesive. Reservoirs 129in the mount 127 provide access to the wells on the working part of thechip. The reservoirs 129 hold much greater volumes of material than thewells in the working part 128, thus providing an interface between themacro-environment of the user and the microenvironment of the wells andchannels of the microfluidic device. Although the use of the plasticmount 127 to hold the working part 128 provides several advantages, theuse of the mount may have some disadvantages. For example, the polymericmaterial of the mount 127 may cause dye interaction and surfacechemistry issues with respect to the materials applied to thereservoirs. Further, mount 127 and the adhesive used to adhere mount 127to the working part may affect the life span of the chip when shippedand stored.

The type of microfluidic chip in FIG. 1 is a “planar” chip. In a planarchip, the only access to the microchannels in the chip is through thereservoirs 129 in the caddy and in-turn through the wells in the workingpart 128. Another type of microfluidic chip is a “sipper” chip, whichhas a small tube or capillary (the “sipper”) extending from the chipthrough which fluids stored outside the chip can be directed into themicrofluidic channels in the chip. Typical sipper chips have between oneand twelve sippers. In use, the sipper is placed in a receptacle havingsample material and minute quantities of the sample material areintroduced, or “sipped” through the capillary tube to the microfluidicchannels of the chip. This sipping process can be repeated to introduceany number of different sample materials into the chip. Sippers make iteasier to carry out high-throughput analysis of numerous samples on asingle microfluidic chip.

Microfluidic chips fabricated from glass are typically shipped afterhaving been preconditioned or “primed” with sodium hydroxide underpressure. The preconditioning process prepares the surface of the chipfor use and increases the lifetime of the chip. The extremely causticnature of the preconditioning fluid makes it desirable to have thepreconditioning performed by technicians prior to shipping as opposed tohaving the end user apply the sodium hydroxide. The chips are thenshipped in liquid to preserve the preconditioned surface state. In manycases, it may also be desirable to precondition or prime microfluidicchips fabricated from polymeric materials, and to ship those chips in aliquid to preserve a preconditioned surface state. Regardless of thechip material, and the surface treatment requirements associated withthat material, microfluidic chips often need to be primed, i.e. filledwith liquid, before they can be used to perform analyses.

Current shipping and storage methods for primed microfluidic chipstypically entail the use of a fluid-filled container. The fluid isgenerally distilled water containing a preservative such as EDTA or abuffer such as tris-tricine. When a chip is placed in a container, it issubmerged in the fluid and suspended in the submerged position. Thistype of shipping container is undesirable for various reasons. First,the end user must “fish” the chip out of the fluid in which it has beenshipped. Secondly, the submersion may weaken the adhesive bondingbetween the laminated substrate layers in the chip, or the bondingbetween the working part of the chip and a mounting fixture holding theworking part of the chip. Those types of delamination may render thechip unusable. Finally, as the chips are capable of being reused manytimes, the user must replace the chips into the storage fluid betweenuses, which increases the risk of contaminating the chip.

Although microfluidic devices have become advanced enough that multipleanalyses can be performed on a single chip using very small volumes ofsample material, the preparation and handling of chips often requires agreat deal of human effort and time. The reservoirs on a chip are alsovulnerable to evaporation and/or current leakage between reservoirscausing changes in concentration of sample materials or in fluid flowthrough the chip, which can make the chip function inaccurately.

Several macro-scale automatic reader and liquid handling devices havebeen developed for transferring material into and out of, and monitoringthe output (e.g. level of fluorescence) of reactions carried out instandard 96, 192, 384 and 1536 well microtiter plates. Such devices areparticularly useful for liquid handling or detection. However, themicrotiter plates used in conjunction with such macro-scale devicesprovide limited functionality as compared with microfluidic devices,since microtiter plates do not allow for the type fluid movement thatcan take place within microfluidic devices. Although the macro-scaledevices designed for used with microtiter plates do have some liquidhandling capability, this capability is not particularly suited for thetypes of operations that can be performed on microfluidic chips.Furthermore, liquid handling devices and automatic readers are notconventionally integrated into a single machine.

BRIEF SUMMARY OF THE INVENTION

The present invention is directed towards an automated microfluidic chipprocessing apparatus.

One aspect of the present invention is an automated microfluidic chipprocessing apparatus including a chip handling system, a fluid controldevice, and a detection system, wherein the chip handling system movesthe chip to the fluid control device and detection system. In one aspectof the present invention, a liquid handling system may be integratedinto the automated microfluidic chip processing apparatus.

Another aspect of the present invention includes a chip that is suitablefor use in the present invention that does not utilize a mountconventionally found on microfluidic chips. Such a chip may have nomount or may use an alternative mount providing for smaller overall chipsize. Yet another aspect of the present invention is a microfluidic chipwith or without a mount having a pierceable film covering at least oneof the reservoirs. Another aspect of present invention is a cartridgefor stacking, distributing and dispensing microfluidic chips, such asfor use with an apparatus of the present invention.

Another aspect of the present invention includes a method of processinga microfluidic chip including providing a microfluidic chip apparatus,including a chip handling system, a fluid control system, and adetection system. The method includes providing at least onemicrofluidic chip including a sample material; positioning the chip withrespect to a fluid control system and a detection system via a chiphandling device; controlling the flow of a material through said chipvia the fluid control system; and detecting results of an assayconducted on the chip via the detection system.

Other aspects of the present invention include the apparatus describedabove having one or more of the following: a priming station, a washingstation, a control system for controlling the apparatus, a data outputsystem, an alignment system and/or the capability of simultaneouslyprocessing more than one chip.

Further features and advantages of the invention, as well as thestructure and operation of various embodiments of the invention, aredescribed in detail below with reference to the accompanying drawings.It is noted that the invention is not limited to the specificembodiments described herein. Such embodiments are presented herein forillustrative purposes only. Additional embodiments will be apparent topersons skilled in the relevant art based on the teachings containedherein.

BRIEF DESCRIPTION OF THE DRAWINGS/FIGURES

The accompanying drawings, which are incorporated herein and form a partof the specification, illustrate the present invention and, togetherwith the description, further serve to explain the principles of theinvention and to enable a person skilled in the pertinent art to makeand use the invention.

FIG. 1A is a top view of a conventional microfluidic chip. FIG. 1B is abottom view of a conventional microfluidic chip.

FIG. 2 is a schematic exploded perspective view of a microfluidic chipof the present invention.

FIG. 3A is a schematic perspective view of an embodiment of an apparatusof the present invention. FIG. 3B is an exploded view of a portion ofthe apparatus of FIG. 3A.

FIG. 4A is a schematic top perspective view of an alternative embodimentof an apparatus of the present invention. FIG. 4B is a schematic topview of the apparatus of FIG. 4A in combination with a top plan view ofa conventional 96-well microplate. FIG. 4C is a schematic topperspective, partial cross-sectional view of the apparatus of FIG. 4A.

FIG. 5A is a schematic perspective view of an embodiment of a chiphandling system of the present invention. FIG. 5B is a schematic topview of an alternative embodiment of a chip handling system of thepresent invention.

FIG. 6A is a schematic top perspective view of an embodiment of a chipcartridge of the present invention. FIG. 6B is a schematic bottomperspective view of an alternative embodiment of a chip cartridge of thepresent invention.

FIG. 7 is a schematic top perspective, partially exploded view of analternative embodiment of the present invention.

FIG. 8 is a schematic top perspective, partial cross-sectional view ofan alternative embodiment of the present invention.

FIG. 9 is a schematic top perspective view of an undiced wafer of thepresent invention.

FIG. 10A is a schematic cross-sectional view of an alternativeembodiment of a microfluidic chip of the present invention. FIG. 10B isa top view of an alternative embodiment of a microfluidic chip of thepresent invention.

The present invention will be described with reference to theaccompanying drawings. The drawing in which an element first appears istypically indicated by the leftmost digit(s) in the correspondingreference number.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed towards an automated apparatus forprocessing a microfluidic chip. An example of a microfluidic chip 204 isillustrated in FIG. 2. The chip 204 shown is the working part of thechip without a mount. In the embodiment shown in FIG. 2, the chip 204includes a bottom plate 212 formed from a solid substrate that issubstantially planar in structure, and which has at least onesubstantially flat upper surface 216. The substrate could be fabricatedfrom a variety of materials such as fused silica, glass, or plastic. Inthis embodiment, the channels and/or chambers of the microfluidic chip204 are formed when grooves 213 in the upper surface 216 of the bottomplate 212, are enclosed when the bottom plate 212 is bonded to a topplate 214. The grooves can be formed in the upper surface 216 of thebottom plate by any fabrication method capable of producing microscalefeatures in the material forming the bottom plate. For example, if thebottom plate 212 is formed from a glass substrate, the grooves could beformed by photolithographically defining the location of the grooves,and then etching the grooves into the upper surface 216 of the bottomplate. If the bottom plate 212 is formed from the plastic substrate, thegrooves 213 could be formed by injection molding or by embossing. Inalternative embodiments, the grooves that will form the channels orchambers could be fabricated in the lower surface 205 of the top plate214, or in both the upper surface 216 of the bottom plate 212 and thelower surface 205 of the top plate 214. Like the bottom plate 212, thetop plate 214 is substantially planar in structure, and can be formedfrom a solid substrate of fused silica, glass or plastic. The top plate214 has both the first surface 205 and a second surface 207 opposite thefirst surface 205. In the microfluidic chip shown in FIG. 2, the topplate 214 includes a plurality of apertures, holes or ports 215 disposedtherethrough, e.g., from the first surface 205 to the second surface207.

When the first surface 205 of the upper plate 214 is placed into contactwith and bonded to the upper surface 216 of the bottom plate 212, thegrooves and/or indentations 213 in the surface of the bottom plate 212are enclosed to form microchannels and/or chambers. The apertures, holesor ports 215 disposed in the upper plate 214 of the chip are orientedsuch that they are in communication with at least one microchanneland/or chamber formed from the grooves or indentations 213 in the bottomplate 212, thus providing external access to the microscale channels andchambers. In other words, the apertures form wells that facilitate fluidor material introduction into the microchannels, as well as to provideports through which electrodes or pressure hoses may apply electricfields or pressure differentials for controlling and directing fluidtransport within the microfluidic chip. The wells typically hold about500-5000 nl and have diameters of about 500 μm to 2000 μm.

The operation of a microfluidic chip includes the movement of materialthrough microchannels arranged on the chip in a controlled manner.Several different methods have been used to control the flow of materialin a microchannel, and each may be incorporated into embodiments of thepresent invention, as a fluid control system. For example, fluidmovement may be controlled by the application of positive or negativepartial pressure to certain reservoirs, so that fluid moves fromlocations of high pressure to locations of low pressure through themicrochannels. Partial pressures may be applied by a pumping mechanismor the application of a vacuum force to a reservoir. Another exampleincludes the use of electro-kinetics, such as electrophoresis orelectro-osmosis, wherein the fluid moves in response to the applicationof positive and negative voltages. Therefore, the fluid control systemincludes the capabilities for providing and controlling forces to movefluids through microfluidic channels.

An embodiment of the apparatus of the present invention also includes adetection system in operation with the chip to provide data regardingthe concentration of one or more materials in a microfluidic channel Thefeatures that a detection system may detect to provide concentrationinformation include, but are not limited to, optical absorbance,refractive index changes, fluorescence emission, chemiluminescence,Raman spectroscopy, electrical conductance, electrochemicalamperiometric measurements, and acoustic wave propagation. These variousdetection methods are discussed, for example, in U.S. Pat. No.5,858,195, the disclosure of which is incorporated herein by referencein its entirety. In one embodiment, the detector system is capable ofdetecting more than one sample material in a microfluidic chip, ifdesired.

Embodiments of the present invention provide systems and methods forautomating these and other aspects of chip handling and operation forincreased accuracy and speed in the biological and chemical analysesperformed on microfluidic chips. For example, FIG. 3A shows an apparatus300 in which multiple microfluidic chips, such as chip 204, can be used.The apparatus includes a deck 302 and a robotic head 306 that is capableof moving in the x-y-z directions across deck 302. Robotic head 306 issuspended from a hood 308 that is supported by supports 310. Deck 302has been divided into universal stations 320. Universal stations 320 maycontain any type of materials, plates, holders, etc., that may be usedduring the microfluidic chip processing.

In the embodiment of FIG. 3A, robotic head 306 also incorporates aliquid handling device. In order for a microfluidic chip to operate,sample and buffer material must be added to the reservoirs on the chip.The liquid handling system provides materials to chip 204 for variousprocedures. The liquid handling device can be any automated apparatusfor transferring liquid. The liquid handling system may transfer liquidfrom bulk storage or may transfer liquid materials from macro-volumereceptacles to a micro- or nano-volume receptacle. For example, a liquidhandling system may be capable of transferring sample material, buffer,or other materials into the micro-, nano-or Pico-volume reservoirs ofthe microfluidic chip 204.

The liquid handling system may be a capillary or other pipetting systemusing a volume control, to aspirate and dispense materials. Examples ofsuch volume controls include, but are not limited to, peristaltic pumps,syringe pumps, solenoid inertial dispensing systems, flowmeters, orpiezoelectric transducer controls. The liquid handling system mayinclude any type of nozzle for directing the material into thereservoirs of the microfluidic chips. One example of a liquid handlingsystem with nano-volume capacity includes an array of stainless steelcannula, each having a ceramic nozzle that can deliver volumes as low as100 nl. U.S. Pat. No. 6,592,825, the disclosure of which is incorporatedby reference herein in its entirety, discloses the transfer of evensmaller volumes of material to and from microfluidic plates, forexample, picoliter volumes, which may be incorporated into the presentinvention. An array of disposable tips may be used or a fixed cannulawith permanent tips. In one aspect of the invention, the liquid handlingsystem may have an interchangeable arrangement of tips and arrays for avariety of liquid handling procedures.

Disposable tips and other features of the liquid handling device may beprovided in one or more of the universal stations 320 provided in deck302. The liquid handling system is generally capable transferringmaterials from any sized receptacle, including but not limited to, aflask, a bulk resource, an eppendorf tube, and wells on a 96-, 192-,384- or 1536-well microtiter plate. As such, in the apparatus shown inFIG. 3A, most universal stations 320 are configured to be about the sizeof a standard microtiter plate. Having stations of this size allows forthe placement of microtiter plates on deck 302, as a source of samplematerial or other materials to be added to the microfluidic chip duringprocessing. As such, the liquid handling device of the apparatus takessample material from a microtiter plate and applies it to a microfluidicchip positioned in a different station 320. Further, known liquidhandling devices currently available for use with microtiter plates maybe appropriate for incorporation into the apparatus of the presentinvention. In other embodiments, some or all of the stations 320 on deck302 are the size of a single microfluidic chip, a microfludic chip mountof a particular size, or an undiced microfluidic chip wafer featuring aplurality of microfluidic chips, as discussed below with respect to FIG.9. Alternatively, stations 320 may be occupied by a holder/adaptor forholding one or more microfluidic chips.

Further, the liquid handling system may include such advanced featuresas the ability to dilute or normalize concentrations of materials in asingle step procedure. The liquid handling system may also be capable ofsupplying consistent small volumes to reservoirs for the formation ofconsistent streams flowing through microchannels. Further, the liquidhandling system may by self-cleaning. In other words, it may have theability to flush the liquid handling device to avoid contaminationbetween different samples. Thus, the liquid handling device is capableof handling a variety of materials at a time, with appropriate washingbetween each material. Further, a liquid handling device of the presentinvention may be capable of providing a sample plug of material in abuffer stream, to process several samples in spaced out intervals on achip 204. Possible sample/pipette configurations include, but are notlimited to: one pipette for a single sample, one pipette for multiplesamples, multiple pipettes for a single sample, and multiple pipettesfor multiple samples. Also, data analysis performed by the liquidhandling system can confirm in real-time whether the current volume ofmaterial has been properly transferred to a reservoir and can performrepeat pipetting, if necessary.

The apparatus 300 includes at least a fluid control system and adetection system, disposed in a single unit 317. In the embodiment ofFIG. 3A, unit 317 is disposed on deck 302, occupying one or moreuniversal stations 320. Head 306 also functions as a chip handing systemto move a chip 204 from a station 320 on deck 302 to the unit 317, wherethe fluid control system and detection system operate on chip 204. Asshown in FIG. 3A, head 306 includes a gripper 321 capable of moving asingle microfluidic chip, several microfluidic chips or other itemsoccupying stations 320. Microfluidic chip 204 is acted upon by a liquidhandling system operated from within head 306. Once the material isloaded on to the chip 204 via the liquid handling system located in head306, head 306 moves chip 204 to unit 317.

Chip 204 may, however, first be moved to a priming station 319 alsopositioned on deck 302. FIG. 3B is a view of two units 317 that includethe fluid control system and the detection system. FIG. 3B also shows apriming station 319 that is used to begin the flow of material throughthe microchannels of chip 204. Microfluidic chips are often primed withgel, buffer or another such material. Chip 204 is then placed in one ofthe two units 317, wherein the desired operation is performed on thechip 204 by the controlled flow of the material through the chip and theresults determined by the detection system.

The apparatus 300 of FIG. 3A may also include a washing or flushingsystem (not shown), where chip 204 and/or the liquid handling system canbe flushed and/or a shaking system, whereby the chip is shaken and anymaterials thereon are mixed or stirred.

FIG. 3B shows a chip 304 positioned in units 317. Chips 304 include achip substrate and a mount. However, a chip 204 without a mount may beused instead, as discussed below in greater detail. In the examplesshown in FIGS. 3A and 3B, electrodes positioned in a hinged lid of units317 are lowered to engage reservoirs of a pre-positioned microfluidicchip. In other embodiments, the fluid control system and detectionsystem may be positioned on deck 302 in other ways. For example, in oneembodiment, these features are disposed in head 306, which moves withrespect to deck 302, such that each feature can access the chip 204 fromabove. In yet another embodiment a liquid handling device is alsopositioned on deck 302 and head 306 functions merely as a chip handlingsystem to move chip 204 from the station or stations occupied by theliquid handling system to the station or stations occupied by fluidcontrol system and detection systems.

Another embodiment of an apparatus of the present invention is shown inFIGS. 4A-4C. FIG. 4A shows an apparatus 400, which includes at least thefluid control system and the detection system, located within a housing433. The apparatus 400 includes a deck 402 onto which a microfluidicchip 204 has been placed. The chip 204 is positioned on a movingconveyor 432, which delivers the chip 204 in the direction indicated byarrow 434 into and out of housing 433. After the microfluidic chip isprocessed, conveyor 432 may move the chip out of housing 433 in adirection opposite where it entered, so that the chip may be disposedinto a receptacle 436. As such, the embodiment shown in FIG. 4A isparticularly useful for disposable microfluidic chips 204 that are notintended to be reused. It is intended, however, that apparatus 400 maybe used with either reusable or disposable microfluidic chips 204.

Apparatus 400 of the present invention does not necessarily incorporatea liquid handling system. In this embodiment, a liquid handling systemmay act upon a microfluidic chip 204 while it is positioned on deck 402,outside of housing 433, as shown in FIG. 4A. Alternatively, liquids maybe supplied by hand to chip 204, or by some combination thereof. Inanother embodiment, a liquid handling system may be integrated intoapparatus 400, such as by having deck 402 be a station in a liquidhandling system. The in and out movement of conveyor 432 allows a chip,for example, to be loaded with material on deck 402, moved into housing433 to be primed by the fluid control system, moved back to deck 402 toreload with sample material, and moved again into housing 433 forprocessing.

FIG. 4B shows a top view of the apparatus 400, showing the placement ofchip 204 on deck 402 and within housing 433. FIG. 4B also shows the sizeof the apparatus relative to a conventional 96-well microliter plate A.It is intended that the apparatus 400 have the same size footprint asconventional microtiter plate A. Since the size of the apparatus 400 isroughly the dimensions of microliter plate A, it may be positioned tooccupy one or more of the universal stations 320 in an apparatus 300such as that shown in FIG. 3A, which integrates a liquid handling systemtherein. In other words, apparatus 400 would replace the unit 317, shownin FIG. 3A.

FIG. 4C shows a schematic perspective view of the working parts of theapparatus 400, which are enclosed in a housing, such as housing 433 ofFIG. 4A. FIG. 4C shows chip 204 positioned on deck 402. In thisposition, chip 204 is accessible to a liquid handling system, ifdesired. In an alternative embodiment, apparatus 400 may have a deckthat slides into and out of housing 433, similarly to a CD playersliding in an out of a dashboard car CD player.

Apparatus 400 includes an upper hood 440. In the example shown in FIG.4C, the upper hood 440 includes a fluid control system, shown in phantomin FIG. 4C as electrode array 444. Meanwhile, below deck 402 lies ahydraulic or pneumatic lift arrangement 446. The lift arrangement 446includes a hydraulic or pneumatic actuator, such as a motor 445 and aplatform 447. When actuated, platform 447 is hydraulically orpneumatically extended in a vertical direction, lifting the chip 204 offdeck 402. Platform 447 may also be hydraulically or pneumaticallyretracted to reposition chip 204 on deck 402. When the platform 447 isin the extended position, chip 204 engages the electrodes 444 of thefluid control system located in the upper hood 440. Thus, the fluidcontrol system only operates upon chip 204 when the chip is pressedagainst it.

In an alternative embodiment, upper hood 440 may instead move in avertical direction to bring the fluid control system into contact withchip 204. In still another embodiment, a hydraulic or pneumatic liftingdevice may be positioned in the upper hood 440, such that the devicepulls the chip 204 toward the electrode array 444 rather than pushingfrom beneath chip 204. Because upper hood 440 is positioned above chip204, a variety of fluid control devices are easily substituted for eachother.

Similarly, a detection system may either be disposed in the upper hood440 along with the fluid control system, or it may be integrated withinthe lift arrangement 446, such as incorporated as part of platform 447.In the embodiment of FIG: 4C, the center of platform 447 includes anoptical detector 443 as part of a detection system. Platform 447 mayalso include a heating and/or cooling system, since the viscosity offluids moving through microchannels is greatly affected by temperaturechanges. The heating and/or cooling system may also includethermocouples for measuring the temperature of fluids in microchannelsand a temperature control system. Further, platform 447 may incorporatean optical alignment system, such at that discussed in detail below withrespect to FIG. 11.

Apparatus 400 includes a chip handling system that features conveyor 432to move chip 204 across deck 402. Conveyor 432 includes a motor 450 thatrotates at least one of a pair of spindles 448 to move a belt 449.Spindles 448 may also be pulleys, gears, or other devices for moving abelt 449. Conveyor 432 also includes at least one car 451 attached tothe belt 449. In this case, car 451 includes a rod 452 that engages anotch 409 in chip 204, to move chip 204 along deck 402.

FIG. 5A shows another embodiment of a chip handling system that could beused in apparatus 400, which includes a conveyer 532 a having a belt 549and spindles 548, one or both of which are rotated by a motor 550.Attached to belt 549 is car 551, into which chip 204 is positioned, suchthat it is pushed along belt 549 from the sides of chip 204 rather thanfrom a notch in the middle of the chip, as shown in FIG. 4C. In oneembodiment, conveyor 432 may use rollers instead of spindles 448 andbelt 449 to move a chip 204. In another embodiment of a chip handlingsystem, in FIG. 5B, a conveyor 532 b may consist of two belts 549 a and549 b for transporting the chip 204 into and out of the housing 433 andpositioning chip 204 on platform 447. In this case, belt 549 a ispositioned under one side of chip 204 and belt 549 b is positioned underthe opposite side of chip 204, such that platform 447 has access to acentral area of chip 204 between belts 549 a and 549 b to lift it. Inthis embodiment, conveyor 532 b of FIG. 5B does not require a car to aidin moving chip 204 along deck 402. In one embodiment, conveyor 532 b mayuse rollers instead of spindles 548 and belts 549 a/549 b to move a chip204.

Each of apparatus 300 and apparatus 400, described herein may beutilized with more than one chip 204 for continuous chip processing.FIG. 4C shows a stack 435 of chips 204. In this manner, microfluidicchips 204 can be processed rapidly and repeatedly without having tomanually load and unload each chip 204. FIG. 4C also shows a bucket 465,into which is inserted a cartridge 460 holding stack 435 of chips 204.Thus, in another aspect of the present invention, microfluidic chips 204are not packaged separately, but are instead packaged in stacks 435 thatare stored in cartridges 460.

FIG. 6A shows an example of a cartridge 660 with chips 204 housedtherein. Cartridge 660 also includes a lid 662, which may be eitherautomatically lifted by an apparatus of the present invention when a newchip is desired or which may have a slot 663 through which each chip 204is accessed. Alternatively, stack 435 could be shrink-wrapped andshipped without an exterior cartridge. Chips may be shipped in apre-primed condition. For example, stack 435 of chips may be loaded withan electrophoresis gel or loaded with a dry material, such as aparticular reagent, which can subsequently be reconstituted prior touse. However, chips may also be stacked and packaged dry, where theapparatus of the present invention includes automated priming of thechips. In the embodiment of FIG. 6A, the cartridge 660 includes a guide670 along the interior 672 of the cartridge 660, and each of the chips204 has a notch 674 slideably mateable with the guide 670.

FIG. 5A further shows how stack 435 may be biased upwards by a spring555, such that as chips 204 are removed from the stack, a new chip 204is pushed up to the deck 402 ready perform the next analysis.Alternatively, as shown in FIG. 6A, stack 435 may be lifted by a secondhydraulic or pneumatic lift device, which includes a platform 666 and apiston 667 wherein the platform is inserted into a bottom end 669 ofcartridge 660 to access the chips. In another embodiment, a cartridge660 a, as shown in FIG. 6B, may have an opening 668 at a bottom end 669to be accessed by the hydraulic or pneumatic lift device. The cartridge660 a is configured to house microfluidic chips 304 that utilize aplastic mount 627. In particular, these mounts 627 may have the samedimensions as a microtiter plate, such that cartridge 660 a may fit in auniversal station 320 in apparatus 300 in FIG. 3A. In yet anotherembodiment, a cartridge with an opening 668 in a bottom end 669 may alsobe positioned above a deck 402. As such, gravity causes the next chip204 to fall onto deck 402 when a bottom chip 204 is removed. In theembodiment of FIG. 6B, each of the microfluidic chips 304 has a planarchip portion 681 and a continuous perimeter 680 perpendicular the planarchip portion 681. The continuous perimeter 680 including a pair ofparallel sides 682 a, 682 b; a first end 684 a connected between thepair of parallel sides 682 a, 682 b; and a second end 684 b connectedbetween the pair of parallel sides 682 a, 682 b opposite the first end684 a, with the first end 684 a having a first end portion 683 a at afirst oblique angle to one of the pair of the parallel sides 682 b and asecond portion 685 a at a second oblique angle to the other of the pairof the parallel sides 682 a. The cartridge 660 a has a cross-sectioncomplementary to the continuous perimeter 680 of each of themicrofluidic chips 304. In this example, the second end 684 b isparallel to the first end 684 a of the continuous perimeter 680.

Returning to FIG. 4C, a similar bucket 436 may be provided for disposingof chips 204 after they have been processed. Bucket 436 may also includean empty cartridge 461, which is filled by the processed chips as theymove along the conveyor 432, such that human contact need only occurwith a cartridge and not the actual chips. Further, bucket 436 mayinclude a washing or flushing system to clean the processed chips, suchthat chips may be easily reused. In another embodiment, bucket 436 maybe connected with bucket 465 via a U-shaped tunnel running underneaththe apparatus (not shown). In this embodiment, once a chip falls intobucket 436 and is washed or flushed, the chip is conveyed by anotherchip handling system so as to be restacked, for example from the bottom,in bucket 465. Constantly recycling chips in this manner providesconstant access to fresh chips without requiring new cartridges forbucket 465.

FIG. 7 shows yet another alternative apparatus 700, which is identicalto that of apparatus 400 except that apparatus 700 includes a removabledeck 702. Deck 702 includes two or more buckets 765 for storing morethan one cartridge of microfluidic chips 204. In the embodiment shown inFIG. 7, for example, there are two buckets 765 for storing twocartridges of chips 204. As such, apparatus 700 may include multiplefluid control systems, multiple detection systems and optionallymultiple liquid handling systems, in order to process multiple chips 204at the same time.

An apparatus of the present invention may also include software tocontrol the operations of an apparatus of the present invention. FIG. 8shows a control unit 890 connected via a cable 891 to an apparatus 800of the present invention, similar to apparatus 400 discussed above withrespect to FIG. 4C. Control unit 890 may include electronics, powersupply, pumps or other pressure controls for the fluid control device,temperature controls for heating or cooling systems of apparatus 800 andother control and operation features, such as for the detection systemand liquid handling devices. Further, control unit 890 may include anynecessary software and a processor including programming for the variouscomponents described above. In one embodiment, an input device (notshown) such as a mouse, display and/or keyboard, is connected to controlunit 890, such that a user can customize the particular procedures priorto and during the processing of a microfluidic chip. Further, softwarewill function with the detection system and/or liquid handling system inorder to produce real-time feedback and display of data. Such data maybe made available through an output device (not shown), which is incommunication with control unit 890, and which may take the form of aprinter, an ethernet connection, a floppy disk or CD-ROM drive, amonitor or other visual display device. Alternatively, each of thefeatures of control unit 890 may be integrated into the apparatus 800itself. However, having an external control unit has the advantage thatthe apparatus 800 may be made smaller, such as to match the size of thefootprint of 96-well microtiter plate A, as discussed above.

Control unit 890 may also be a universal control unit. As such, controlunit 890 may be used with a variety of microfluidic chip processingapparatuses, which may function in different ways or be particularlydesigned for specific chemical or biological analyses.

A chip 204, as shown in FIG. 2, for use with an apparatus of the presentinvention may not require the plastic mount 127 shown in FIG. 1.Accurate liquid handling and the reduction of human interaction makesthe plastic mount 127 unnecessary. Thus, manufacturing time and partsare reduced, creating more efficient manufacturing, packaging andstoring of microfluidic chips 204.

There are further advantages to removing mount 127. For example, becausethere is no adhesive used to attach the substrate to the mount, it iseasier to determine the shelf life of the chip. Further, potential dyeinteractions with the mount are potentially eliminated.

Since microfluidic chip 204 can be washed and/or primed at the point ofuse by apparatus 300/400, the chips can be stored or shipped dry forimproved aging and lifetime, as well as reduced shipping and storagecosts. Also, polymer mounts and adhesives are known to contaminatesamples, which could make some conventional chips 104 unsuitable for usewith mass spectrometers. However, without mount 127, one possibleimpediment to interfacing chip 204 with a mass spectrometer iseliminated.

As shown in FIG. 9, microfluidic chips 204 are often made several at atime on a glass, silica or plastic wafer 970. For most applications,wafer 970 is diced to form individual chips 204. However, in anembodiment of the present invention, an apparatus, such as apparatus 300and 400 described in detail above, may act upon more than one chip 204at a time by acting on a undiced wafer 970. For example, an undicedwafer 970 may occupy a universal station 320 of the apparatus 300 ofFIG. 3A. Similarly, an undiced wafer 970 rather than a single chip maybe transported by conveyer 432 in apparatus 400 of FIG. 4C.

Small volumes of material are vulnerable to evaporation. Thus, FIG. 10Ashows yet another microfluidic chip 1004 that is suitable for use in anapparatus of the present invention. Chip 1004 is similar to chip 204 ofFIGS. 2A and 2B in that it has a first plate 1012 including amicrochannel 1013 and a second plate 1014 having a reservoir 1015 boredtherein. Chip 1004, however, also includes a film 1075 adhered to asurface 1007 of second plate 1014. Film 1075 covers at least reservoirs1015, and may cover the entire chip 204, as shown in FIG. 10A. Film 1075is a pierceable film, which can be pierced by a cannula or tip of aliquid handling device or by the application of heat, e.g. IR. As such,the film 1075 is pierced at the point when the material is added to thereservoir(s) 1015, forming only a very small hole accessing reservoir(s)1015. Thus, evaporation from reservoir(s) 1015 is minimized Also, film1075 maybe a self-sealing film, such as a split septum, such that asmall piercing for the purpose of filling reservoir 1015 may be resealedwhen the tip or cannula of a liquid handling device is removed.

Further, film 1075 may provide electrical isolation between reservoirs1015 that are located close together. For example, if electrodes engagechip 1004 as part of the fluid control system, the electrode will alsopierce film 1075 in more than one reservoir 1015 location. As such, thefilm 1075 will act as an insulator between adjacent electrodes. As analternative, concentric trenches may be partially etched into the secondplate 1014 to increase the path length and thus the electrical impedancefrom reservoir to reservoir. Still further, the film 1075 may serve as agasket for pressurized priming and washing of chip 1004.

FIG. 10B shows yet another microfluidic chip 1004a of the presentinvention that includes a mount 1027. Since a chip 1004a that is used inan apparatus of the present invention does not require human handling,mount 1027 may be roughly the size of the microfluidic chip itself, andthus much smaller than a conventional mount 127, shown in FIG. 1. Mount1027 includes wells 1028 to aid in the application of materials to chip1004a by either a liquid handling system or a human operator. Further,mount 1027 provides an external location for a notch 1009 to be used fora car of a conveyor to engage the chip. Thus, such a notch 1009 need notbe made in the microfluidic chip itself.

An apparatus 300/400 of the present invention may also include analignment system to ensure that a liquid handling system, fluid controlsystem or the detection system is properly aligned with a particularreservoir of a microfluidic chip. In an example of an alignment systemin accordance with the invention, the reservoirs of a microfluidic chipare formed from non-opaque holes in a generally opaque second plate,which is bonded to a transparent first plate. Therefore, visibleemission of light from a source will only be visible from an opticalsensor, when the light is positioned directly below a reservoir of thechip. Thus, an optical sensor can detect when it is properly alignedwith a reservoir, and when reservoir is properly positioned on a deck.Once one reservoir is detected, the locations of all additionalreservoirs may be computed. Larger multi-chip wafers 970, such asdiscussed above in FIG. 9, reduce the amount of alignment necessary. Asimilar alignment system is described in U.S. Pat. No. 6,592,825, whichis incorporated herein by reference in its entirety. Other types ofsensors, as would be apparent to one skilled in the relevant art, may beused in a similar manner to indicate proper alignment of a microfluidicchip in an apparatus of the present invention.

Embodiments of the present invention also include methods for processinga microfluidic chip using an apparatus in accordance with the presentinvention. For example, one method includes a first step of providing anapparatus, as discussed above that includes at least a chip handlingsystem, a fluid control system, and a detection system, and at least onemicrofluidic chip, which may be provided in a cartridge or as part of anundiced wafer. Further, a sample material must be loaded onto themicrofluidic chip, such as by the use of an optional liquid handlingdevice. Then, the apparatus is programmed to control the flow of thesample material through the microfluidic chip in a predeterminedarrangement via the fluid control system, and to detect data from anassay at a predetermined location along a microchannel of themicrofluidic chip via the detection system, as discussed above withrespect to the figures.

While the invention has been particularly shown and described withreference to preferred embodiments thereof, it will be understood bythose skilled in the art that they have been presented by way of exampleonly, and not limitation, and various changes in form and details can bemade therein without departing from the spirit and scope of theinvention.

Thus, the breadth and scope of the present invention should not belimited by any of the above-described exemplary embodiments, but shouldbe defined only in accordance with the following claims and theirequivalents.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art (including the contents of thereferences cited herein), readily modify and/or adapt for variousapplications such specific embodiments, without undue experimentation,without departing from the general concept of the present invention.Therefore, such adaptations and modifications are intended to be withinthe meaning and range of equivalents of the disclosed embodiments, basedon the teaching and guidance presented herein. It is to be understoodthat the phraseology or terminology herein is for the purpose ofdescription and not of limitation, such that the terminology orphraseology of the present specification is to be interpreted by theskilled artisan in light of the teachings and guidance presented herein,in combination with the knowledge of one of ordinary skill in the art.

The invention claimed is:
 1. A cartridge for use with a microfluidicchip processing apparatus, the cartridge comprising: a container havinga bottom end defining a bottom opening; and a stack of microfluidicchips disposed in the container above the bottom opening, each of themicrofluidic chips having a planar chip portion a continuous interiorperimeter and a continuous exterior perimeter; both of the perimetersare perpendicular to the planar chip portion and defined by: a pair ofparallel sides, a first end connected between the pair of parallelsides, and a second end connected between the pair of parallel sidesopposite the first end, the first end having a first end portion at afirst oblique angle to one of the pair of the parallel sides and asecond end portion of the at a second oblique angle to the other of thepair of the parallel sides; wherein gravity moves a bottom one of thestack of microfluidic chips to the bottom opening when a preceding oneof the stack of microfluidic chips is removed downwardly through thebottom opening by the microfluidic chip processing apparatus, and thecontainer has a cross-section profile complementary to the continuousexterior perimeter of each of the microfluidic chips.
 2. The cartridgeof claim 1 wherein each of the microfluidic chips includes a mount. 3.The cartridge of claim 1 wherein the second end is parallel to the firstend.
 4. A microfluidic chip processing system comprising: a microfluidicchip processing apparatus comprising: a housing; a microfluidic chipprocessing area comprising a fluid control system and a detectionsystem, wherein the fluid control system and the detection system aredisposed within the housing, the fluid control system having a fluiddriver operable to control fluid motion through one or more channels ofa microfluidic chip; a microfluidic chip storage area spaced apart fromthe microfluidic chip processing area, the microfluidic chip storagearea including a receptacle; and a microfluidic chip handling systemcomprising a conveyor, at least a portion of which extends between thestorage area and the processing area, the conveyor having a car operableto engage a side portion of a microfluidic chip disposed in the storagearea, the car delivering the microfluidic chip into the housing suchthat the microfluidic chip is in position to be operably coupled withthe fluid control system and the detection system; and a cartridgecomprising: a container having a bottom opening; and a stack ofmicrofluidic chips disposed in the container, each of the microfluidicchips having a planar chip portion a continuous interior perimeter and acontinuous exterior perimeter; both of the perimeters are perpendicularto the planar chip portion and defined by: a pair of parallel sides, afirst end connected between the pair of parallel sides, and a second endconnected between the pair of parallel sides opposite the first end, thefirst end having a first end portion at a first oblique angle to one ofthe pair of the parallel sides and a second end portion at a secondoblique angle to the other of the pair of the parallel sides; whereingravity moves a bottom one of the stack of microfluidic chips to thebottom opening when a preceding one of the stack of microfluidic chipsis removed through the bottom opening by the microfluidic chipprocessing apparatus, and the container has a cross-section profilecomplementary to the continuous perimeter of each of the microfluidicchips; wherein the receptacle is sized to receive the cartridge.
 5. Thesystem of claim 4 further comprising a reservoir exterior to at leastone of the microfluidic chips and in fluid communication with a channeldisposed within the at least one of the microfluidic chips, thereservoir being operable to receive material from the at least one ofthe microfluidic chips.
 6. The system of claim 4 wherein the car engageseach of the microfluidic chips in series to dispense the microfluidicchips in series.
 7. The system of claim 4 wherein each of themicrofluidic chips includes a mount.
 8. The system of claim 4 furthercomprising a data output system operable to receive data from themicrofluidic chip processing apparatus.
 9. The system of claim 8 whereinthe data output system is selected from the group consisting of aprinter, an ethernet connection, a floppy disk, a CD-ROM drive, amonitor, and a visual display device.
 10. The system of claim 4 whereinthe microfluidic chip processing apparatus has a footprint ofapproximately the same size as the footprint of a standard 96-wellmicrotiter plate.
 11. The system of claim 4 wherein the second end isparallel to the first end.